The present invention relates to pharmaceutical dosage forms comprising a low-solubility drug and a polymer.
It is known in the art that a low-solubility drug may be combined with a polymer to increase the concentration of dissolved drug in an aqueous use environment relative to a composition that does not contain the polymer. For example, Curatolo et al., U.S. Pat. No. 6,548,555 B1, disclose compositions comprising a basic drug admixed with a polymer selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropylmethyl cellulose acetate phthalate (HPMCAP), and methyl cellulose acetate phthalate (MCAP). The basic drug, when administered to a gastric use environment, initially dissolves to a high concentration. This high concentration is sustained by the presence of the polymer when the drug enters a higher pH intestinal use environment.
Curatolo, et al., US published patent application 2002/0006443A1, disclose mixtures of solubility-improved forms of drugs and a polymer. The solubility-improved form may be crystalline, such as a high-solubility salt or polymorph, that provides, at least temporarily, enhanced aqueous solubility relative to the lowest-energy crystalline drug form.
Curatolo, et al., US published patent application 2003/0072801 A1, disclose several solubilized drug forms combined with various polymers. The application discloses, among other things, such solubilized drug forms as nanoparticles and cyclodextrin complexes combined with polymers.
While not wishing to be bound by a particular theory, it is believed that the polymer, when combined with a solubilized drug, generally does not have the capacity to greatly solubilize insoluble drugs (that is, to increase the equilibrium solubility of free drug). Instead, it is believed the polymer primarily acts to slow the rate of precipitation or crystallization of the drug after the drug is initially dissolved. The presence of the polymer(s) thus allows the initially increased or enhanced concentration provided by the solubility-improved form of the drug to be at least partially maintained for at least a few minutes and, in some cases, for many hours. In addition, in cases where dissolution of the solubility-improved form of the drug is slow and precipitation of the low-solubility drug form, in the absence of the polymer, is fast, the presence of the polymer may result in the maximum concentration of drug observed being substantially higher than that observed in the absence of the polymer.
One possible mechanism for improving the dissolved drug concentration involves the association of the polymer and dissolved drug to form “polymer/drug assemblies.” Such assemblies may constitute various forms, including polymeric micelles, high-energy polymer-drug aggregates ranging in size from a few nanometers to 1000 nanometers, polymer-stabilized drug colloids or polymer/drug complexes. An alternative view is that as dissolved drug begins to precipitate or crystallize from solution (e.g., as nucleation begins) the polymer adsorbs to these drug aggregates or nuclei, preventing, or at least retarding, the nucleation or crystal-growth process. In any case, the presence of the polymer serves to enhance the amount of drug that is dissolved or at least available for absorption. The various drug/polymer assemblies listed above are apparently quite labile and may contribute to the drug absorption process.
However, when the low-solubility drug and polymer are mixed together with other excipients to form a dosage form, the polymer and drug may become segregated or diluted relative to each other during manufacture of the dosage form. When the dosage form is then subsequently administered to an aqueous use environment, such as an in vitro dissolution test or the gastrointestinal tract of an animal, the drug and polymer may not be immediately adjacent to one another, which may impede the formation of polymer/drug assemblies. Alternatively, the dosage forms may provide variable performance due to segregation of the drug and polymer during manufacture. In addition, even when the polymer and drug remain uniformly mixed, during dissolution of the drug, the concentration of dissolved drug near the surface of the drug particles may exceed its equilibrium value and begin to precipitate or crystallize prior to encountering sufficient levels of dissolved polymer or polymer-colloids to inhibit such crystallization or inhibition.
Accordingly, it is desired to combine a low-solubility drug and precipitation-inhibiting polymer in a dosage form in a manner that facilitates reproducibly achieving concentration-enhancement of dissolved drug in a use environment, and/or provides or sustains higher concentrations of dissolved drug.